PROJECT SUMMARY/ABSTRACT (30 lines limit) Schizophrenia (SZ) is one of the most debilitating, life-long mental illnesses with profound societal costs. Current treatment has a limited impact in restoring real-life functions. Biological research in the SZ diathesis has provided evidence of deficits in human brain morphology, function and in vivo biochemistry with altered glutamate (Glu) transmission (with the medial temporal lobe being the primary implicated area) emerging as one leading pathophysiologic hypothesis. Glutamatergic hypo-function, associated with diminished N-methyl- D-aspartate receptor function, may reduce hippocampal functionality, in turn driving learning and memory deficits in SZ that others and we have documented. Given that altered functionality may be related to altered biochemistry of the hippocampus, in this proposal we establish a conceptual framework integrating multi-level deficits in network function and the in vivo biochemistry of Glu in the context of a specific domain mechanism, specifically associative learning and memory. These efforts, consistent with NIMH's R-DoC initiative, are critically important in advancing the science of multimodal brain imaging in the service of clinically relevant questions. In particular, we seek to establish the neurobiological bases of learning deficits in SZ, and their impact on illness progression. We introduce (with compelling preliminary data) the application of in vivo H functional MRS (fMRS), a highly novel method for quantitating the modulation of Glu in real-time in the hippocampus, while subjects engage in an associative learning and memory task that we have established as a robust and specific frontal- hippocampal challenge, of particular relevance to SZ. This focus on biochemical dynamics in hippocampal function is an innovation of substantial clinical relevance, particularly as it will be coupled with within- participants acquisition of fMRI data to characterize brain network dynamics and effective connectivity. Using a cross-sectional study design, we will assess the extent and progression of Glu dysfunction and altered network dynamics in early-course and chronically ill SZ patients. In addition to acquiring in vivo H fMRS and fMRI data, we will also acquire basal (non-task active) Glu levels in the hippocampus and dorsolateral PFC (dlPFC) with in vivo H MRS. Our goal is to uncover the mechanisms of brain network and Glu dysfunction in the frontal-hippocampal circuit of SZ patients by demonstrating dlPFC Glu deficits and frontal-hippocampal network dysfunctions impacting hippocampal Glu modulation related to frontal-demanding memory formation in SZ. Additionally, the hippocampal Glu modulation, frontal-hippocampal basal (non-task active) Glu levels and impaired network dynamics will be highly sensitive to illness chronicity evidence by progressive Glu dysfunction with illness duration. If confirmed, these novel methods have the potential of testing directly the efficacy of Glu agonists in ameliorating hypo-modulation of hippocampal Glu in SZ patients as the next step.